The Official Newsletter of the California Poison Control System
Volume 1, Number 3.
Diagnosis and Treatment of
Pediatric Iron Ingestion
Iron is essential for normal tissue and organ function. In toxic doses, iron salts (ferrous sulfate, fumarate or gluconate) cause corrosive gastrointestinal effects followed by hypotension, metabolic acidosis, and multisystem failure.
Many medicinal products contain iron salts, in amounts (expressed as elemental iron equivalents) ranging from 12 to 33% (see Table). Recent studies have demonstrated a positive correlation between incidence of pediatric iron poisoning and recent pregnancy in the household.
The minimum toxic dose of iron in children is estimated to be anywhere from 20-60 mg/kg. Fatal poisonings have rarely been reported with less than 60 mg/kg elemental Fe. A 10-kg toddler can ingest 10 tablets of a 20% elemental Fe preparation (ferrous sulfate), resulting in an ingestion of 65 mg/kg of Fe.
Iron causes severe gastrointestinal symptoms from direct contact of iron with the GI tract. Severe metabolic acidosis and multi-system organ failure may follow, as absorbed iron exerts toxic effects on the cellular level.
Elemental Iron Content of Common Preparations Ferrous gluconate 11.6% Ferrous lactate 19% Ferrous sulfate 20% Ferrous chloride 28% Ferrous fumarate 33% Iron dextran 50mg Fe/mL
A 3 year old female was brought to the Emergency Department (ED) because of gastrointestinal distress. Symptoms began with cramping at mid-day, followed by worsening vomiting and diarrhea throughout the afternoon. No fevers were reported at home. Possible ill contacts were reported at the child’s daycare center. In the ED, the child was noted to be tired-appearing with temperature 36.5°C; pulse 125/min; respirations 30/min; and blood pressure 93/55 mm Hg. She was administered an intravenous saline bolus, 20 mL/kg. Plain abdominal films revealed a non-specific bowel gas pattern and possible evidence of radiopaque material. Laboratory studies revealed: WBC 11,000/mm3 without left shift; hemoglobin 11.9 g/dL; platelets 390,000; sodium 136, potassium 3.9, chloride 112, bicarbonate 19, glucose 103. After 3 hours of fluid resuscitation, the child had increased activity level, with stable vital signs and a resolution of her vomiting. Repeat plain abdominal films revealed a non-specific bowel gas pattern. Although she still complained of mild abdominal pain, she was able to tolerate an oral challenge of fluids. The patient was discharged with the diagnosis of gastroenteritis and instructions to return to the ED for any worsening of symptoms.
Around 6 hours later, the child returned to the ED with complaints of lethargy, pallor, vomiting, and abnormal respirations. Vital signs were temperature 36.5°C; pulse 170; respirations 40; and blood pressure 85/40. Fluid resuscitation was re-instituted, and laboratory studies were repeated: WBC 10,000/mm3 without left shift; hemoglobin 8.1 g/dL; platelets 325,000; sodium 133, potassium 3.7, chloride 104, bicarbonate 5, glucose 110. Arterial blood gases: pH 7.17, PCO2 33 mm, PO2 300 mm on facemask oxygen. Serum iron level was 12,660 mcg/dL (normal 80-180 mcg/dL). Other studies revealed AST 550, ALT 790, and INR 4.1. Further history revealed that the mother gave birth to a new baby 1 month ago.
Despite IV fluids, the blood pressure dropped to less than 70 mm/Hg systolic, and a dopamine infusion was initiated. The child was transferred to the pediatric intensive care unit where she was intubated secondary to declining mental status and worsening serum pH. Transfusion of packed red blood cells was given. Chelation treatment with intravenous deferoxamine was initiated. Plain radiographs again revealed a non-specific gas pattern. Chest X-Ray showed evidence of acute pulmonary injury and edema. Difficulties with oxygenation ensued, with a progressively widening arterial-alveolar gradient. After 24 hours of intensive treatment, the patient expired. A repeat serum iron level 6 hours after admission to the PICU was 14,950 mcg/dL. An empty container of iron supplements was subsequently found in the child’s playroom at home.
1. Why did this patient’s symptoms seem to resolve after the first visit to the ED, leading to the misdiagnosis of gastroenteritis?
2. Shouldn’t the WBC count and serum glucose level be significantly elevated in cases of severe iron poisoning?
From 1999-2001, 10852 cases of iron poisoning were reported to the American Association of Poison Control Centers (AAPCC), with 60% occurring in children under the age of 6 years. Patients presenting to heath care facilities with minor symptoms of poisoning accounted for 75% of cases; patients with moderate symptoms accounted for 21.5% of cases; and patients with severe symptoms accounted for 2.5% of cases, and there were 3 deaths. About 30% of all pediatric pharmaceutical-related deaths reported to the AAPCC during that time period were a result of iron ingestion. Since 1997, the FDA has mandated child-proof strip packaging and warning labels to be placed on all iron-containing products as part of an educational initiative to warn families about the dangers of pediatric iron poisoning. Severe iron toxicity can be fatal in children, especially when diagnosis is delayed. Despite measures to regulate dispensation and packaging of iron-containing products, iron ingestion remains the leading cause of death from poisoning in children under the age of 6 years.
Initial signs and symptoms of iron toxicity result from direct corrosive effects of iron on the gastrointestinal mucosa. Emesis and stools may or may not be bloody. Changes in vital signs are due primarily to volume losses, as well as vasodilation due to absorbed iron. Some degree of metabolic acidosis may ensue secondary to lactate production from dehydration.
Following absorption of toxic doses of iron, the portal vein transports iron to the liver. As iron exits the portal triad and comes into contact with hepatocytes, immediate damage occurs, leading to hemorrhagic periportal injury and necrosis. This pattern of injury is in contrast to acetaminophen-induced centrilobular hepatic necrosis, in which the liver converts the parent drug into a toxic metabolite.
Excess iron in the blood stream is converted from the ferrous (Fe2+) form to the ferric (Fe3+) form. Ferric iron builds up in cellular mitochondria and attracts electrons from the electron transport chain, disrupting oxidative phosphorylation. The pool of hydrogen ions (H+) earmarked for the conversion of ADP to ATP is liberated, exacerbating metabolic acidosis.
Multisystem failure from iron poisoning results from cell death and tissue necrosis secondary to injury to the GI mucosa, the liver and the lung. Elevated tissue levels of iron may also be found in the kidneys and brain.
The classic description of iron poisoning is divided into five distinct “stages”. Stage I describes the vomiting, diarrhea, and abdominal pain resulting from the direct effects of iron on the GI mucosa in the first 6 hours of toxicity. Stage II is called a “latent” period during which patients can experience an apparent recovery that may last 6-18 hours. Stage III involves the clinical picture of shock from volume losses, decreased tissue perfusion, and metabolic acidosis within the first 24 hours. Mental status changes, abnormal respirations, and seizures may occur. Stage IV encompasses the hepatic injury, characteristically apparent clinically and biochemically 2-3 days after exposure. Stage V labels the gastrointestinal strictures and scars that manifest weeks after exposure.
Although often described in textbooks, distinct “stages” rarely occur in such rigid fashion. In fact, Stage II may not occur at all. The reason for the “resolution” of symptoms in Stage II is that patients presenting in Stage I often receive aggressive fluid resuscitation. As the absorbed iron is converted from Fe2+ to Fe3+, patients enter Stage III. Patients may go directly from Stage I to Stage III if they do not receive appropriate therapy, and this transition can occur well before the described time frames. Stage IV (hepatic injury) can be concurrent with the symptoms of shock and metabolic acidosis of Stage III. The bottom line is that the progression of symptoms in iron poisoning is quite fluid.
Iron poisoning should be considered in any patient with GI symptoms, mental status changes, and an unexplained anion-gap metabolic acidosis. Anemia may or may not be present at the time of presentation, and bloody emesis or stools may not be reported. Some sources suggest WBC elevations greater than 15,000/mm3 and blood glucose levels greater than 150 mg/dL as predictive parameters for an iron level greater than 300 mcg/dL, but these predictors have not been validated.
After the clinical diagnosis has been made, a serum iron level is used to follow the progression of the patient’s status. Initial levels may not accurately predict the severity of toxicity, and may rise during treatment if a significant amount of iron remains in the GI tract. Patients with serum iron levels lower than 300 mcg/dL are rarely symptomatic. Total iron binding capacity (TIBC) is listed in many sources as a useful laboratory parameter to evaluate the severity of iron toxicity; however, controlled studies have shown TIBC to be an unreliable laboratory index of iron poisoning.
Radiographically, one often sees evidence of radio-opaque pills or pill fragments in the GI tract. While the presence of such findings may be useful, the absence of positive findings does not completely eliminate the possibility of iron poisoning, because elixir preparations and chewable tablets are not visible on X-Rays. Studies reveal that less than 5% of cases of ingestion of chewable iron preparations are marked by positive identification of pill fragments on X-Rays; however chewable iron preparations rarely cause serious toxicity.
Symptomatic and general supportive treatment is the most important initial intervention in iron poisoning, with close monitoring of vital signs and aggressive intravenous fluid resuscitation. Initial laboratory studies should include complete blood count, electrolytes, and serum iron level. Blood gases, liver enzymes, and prothrombin time may be useful in patients who continue to be symptomatic. Conservative observation is of the utmost importance in resuscitated patients whose symptoms seem to resolve in the ED. Patients who are asymptomatic on arrival in the ED should be observed for at least 4 hours; a workup should be initiated with the onset of any GI symptoms.
Patients who present early in the course of their toxicity may benefit from gastrointestinal decontamination measures. Syrup of ipecac is not recommended because it aggravates GI volume losses and invalidates one of the most important symptomatic monitoring parameters, namely vomiting. Activated charcoal does not bind to iron. Gastric lavage is generally ineffective because intact pills are unlikely to be retrieved, and it may present some risk to the patient with severe gastric injury from iron. Whole bowel irrigation using a balanced polyethylene glycol-electrolyte solution (eg, GoLYtely, Co-Lyte) is the ideal gastric decontamination method because it forces the unabsorbed iron through the GI tract quickly and helps prevent further absorption of iron. It is indicated if the plain x-ray of the abdomen is positive for numerous pills or pill fragments, or possibly if there is suspicion of massive iron ingestion despite a negative or equivocal x-ray and serum levels continue to rise despite treatment.
Very ill patients may benefit from the use of intravenous deferoxamine (DFO). DFO chelates Fe3+ ions to form the complex ferrioxamine, which is renally excreted, frequently imparting a reddish brown (classically described as “vin rose”) color to the urine. Patients with metabolic acidosis, mental status changes, or shock should be considered for DFO therapy. Although many sources suggest iron levels of >500 mcg/dL as an indication to start DFO therapy, one should base therapy primarily on symptoms rather than absolute numbers. Only about 8.5 mg of free ferric iron is chelated by every 100 mg of deferoxamine administered, indicating that the effect of deferoxamine on iron clearance is not significant, and clinical results are often inconsistent. Aggressive supportive care is at the core of treatment of all cases of iron poisoning.
DFO therapy begins with an intravenous infusion of 15 mg/kg/h. Higher doses (up to 30-45 mg/kg/h) may be needed in some cases, but the rate of infusion can be limited by histamine-mediated hypotension in some cases. Duration of therapy has not been well defined, although patients who are projected to recover from iron poisoning generally do so in about 24 hours. Case reports of respiratory distress syndrome and sepsis associated with prolonged high-dose deferoxamine therapy have led to recommendations for early discontinuation of the infusion (within 36 hours), although a strong cause-and-effect relationship has not been established. Change of the color of the urine back to normal may also be an indicator of resolution of toxicity, since this may be indicative of no more free, chelatable iron left to excrete. However, the resolution of symptoms is the best measure to evaluate therapeutic success and endpoints.
Discussion of case questions
This patient received adequate fluid therapy in the early phase of her toxicity. As a result, her symptoms resolved for several hours, as the metabolic phase of her poisoning was beginning to develop. Serum glucose levels and WBC count have not been validated as useful laboratory indicators of the severity of iron poisoning. Both can be normal in very severe cases.
Consultation with a specialist in poison information or with a medical toxicologist can be obtained free of charge by calling the California Poison Control System at 1-800-411-8080.
This issue of CALL US... was written by Cyrus Rangan, MD, FAAP.
CALL US... is published by the California Poison Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors Timothy E. Albertson, MD, Richard Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors Judith Alsop, PharmD, Thomas E. Kearney, PharmD, Anthony Manoguerra, PharmD. Managing Editor: Susan Kim, PharmD
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